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NEUROSCIENCE Old-line Antibiotic Seen to Save Neurons Minocycline Findings May Be Applied to Stroke, Neurodegenerative Disease Medicinal compounds can have nine lives; indeed, the pages of medical journals are filled with accounts of drugs developed for one disease and found to be salve for another. Take minocycline. Developed as an antibiotic 30 years ago, it was later discovered to ease acne, rheumatoid arthritis, and other inflammatory conditions. A few years ago, this common antimicrobial was shown to slow and even limit the neuronal damage caused by stroke and Huntington's disease in mice. But the key to this latest incarnation--how, exactly, it works in the brain--was shrouded in mystery. Minocycline calms mitochondria. Stress signals can cause mitochondria to swell, setting off a deadly chain reaction. Cytochrome c is released into the cytoplasm, where it teams up with other proteins (apaf-1 and procaspase-9). Once bound, caspase-9 signals caspase-3 to deliver its death blow. Minocycline breaks this chain by preventing mitochondria from swelling. (Image by Jeff Cleary) Shan Zhu, Robert Friedlander, and their colleagues have recently discovered that minocycline helps to protect mice from yet another neurodegenerative illness, amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease. What is more, the researchers report in the May 2 Nature, they have figured out the secret behind minocycline's neuron-saving powers--a discovery that could lead to new approaches to treating ALS and Huntington's as well as brain trauma and stroke. Though neurons fall sick for different reasons in each of these diseases, they all die in the same way--cellular messengers signal an enzyme, caspase-3, to cut the cell's DNA. One of these messengers, cytochrome c, is normally sequestered inside the mitochondria. When stimulated, mitochondria swell, giving cytochrome c the opportunity to escape into the cytoplasm. There, it teams up with another protein that signals the caspase to deliver its blow. Minocycline appears to work by stopping mitochondria from swelling and releasing the cytochrome c death messenger. "From a mechanistic point of view, that is the very exciting finding," said Friedlander, HMS associate professor of neurosurgery at Brigham and Women's Hospital. It is exciting, in large part, because of its therapeutic implications. With the cost of developing new drugs so high and the success rate so low, pharmaceutical companies have been searching their shelves to see if they can find existing compounds that may have new uses. The possibility that minocycline--a Food and Drug Administration-approved drug--might slow the development of ALS and Huntington's in humans is enormously attractive. Even more exciting, the discovery of a mechanism--stopping mitochondrial swelling--means that other existing compounds may do what minocycline does, only better. "The exciting thing is finding this antibiotic that comes from left field, and it works in all these diseases. And now we find out how it works," said Robert Friedlander (center), shown with co-authors Shan Zhu (left) and Martin Drozda. (Photo by Graham Ramsay) On their own, even the best of these mitochondria-calming drugs will not be able to stop disease. "This is not a cure," he said. "It will slow the disease." But by staving off cell death, minocycline and drugs like it might keep sick cells alive long enough to allow other drugs to restore them to health. "Our ultimate aim will be to give cocktails, which target different aspects of disease," Friedlander said. "We need to find many different mechanisms and how different compounds will affect them, and put them together. That is where we will get a big impact." The Minocycline Surprise Like most episodes in science, the discovery of minocycline's death-defying powers owes a certain amount to luck, as well as logic. Several years ago, Friedlander and his colleagues discovered that they could lessen brain damage and prolong life in mice with a variety of neurological conditions--trauma, stroke, Huntington's disease, and ALS--by giving them a drug that blocked a member of the caspase family, caspase-1 (see Focus April 21, 2000). But the drug was highly toxic. Searching for something safe, preferably an FDA-approved drug, they came across a report by a Finnish group that had used minocycline to block caspase-1 in mice with strokes. The treated mice had less brain damage. Thinking that minocycline's ability to block caspase-1 might be interfering directly with the cell's apoptotic machinery, rather than its inflammatory apparatus, Friedlander and colleagues gave minocycline to mice with Huntington's disease. Although inflammation plays a role in the disease, the vast majority of neurons die by caspase-mediated apoptosis. Sure enough, the minocycline mice developed symptoms more slowly and lived longer than untreated mice (see Focus July 14, 2000). To confirm that minocyline was acting on the apoptotic machinery, Zhu, HMS research fellow in neurosurgery, Friedlander, and colleagues gave minocycline to mice with another caspase-mediated disease, ALS. The disease progressed more slowly and the mice lived on average 10 percent longer than untreated mice. To exclude the still niggling possibility that minocyline's powers were due to a quelling of inflammation, they induced apoptosis in cultured neurons using three different methods, none of which entailed inflammation. Minocycline kept the cells alive. What is more, they found that the activation of caspase-3 and caspase-9 and the release of cytochrome c had been inhibited. To find out which was being directly targeted, the researchers purified brain and liver mitochondria and stimulated the organelles to release cytochrome c. They then added minocycline. The more they added, the less cytochrome c was released. The clincher came when they found that the addition of minocycline inhibited mitochondrial swelling. Friedlander went back and analyzed the mitochondria in the neurons of his ALS and stroke mice and found that those treated with minocycline released less cytochrome c. "So the important thing is that we show this at three levels--in vivo, in cells, and in isolated mitochondria," he said. The push is on to see if it works in humans. Phase I clinical trials are under way to see if long-term minocycline use is safe in Huntington's disease patients. And momentum is building to test it in ALS patients. One encouraging sign is that a drug now used by Huntington's patients started out by working in mice, and "that is promising," Friedlander said. --Misia Landau